The Life Span of a Rodent May Aid Human Health

Tuesday

Oct 27, 2009 at 4:20 PM

A tunnel-dwelling species seems to have an immunity to cancer and a life span of extraordinary length for a rodent.

NICHOLAS WADE

They live in underground colonies with a queen, her harem of favorite males, soldiers to defend the tunnel system and workers to keep excavating in search of food. But despite having the social structure of an ants’ nest or beehive, naked mole rats are mammals about the size of a mouse. And among their many peculiarities are features that could, if understood, be of great relevance to human health and longevity.

Their life span is of extraordinary length for a rodent. Mice live a couple of years but mole rats can reach the venerable age of 28. The long life is probably a consequence of their protected existence. Mice have a short life span because they have many predators. Better to breed fast and young than prepare for an old age none will never live to see. Gray squirrels, on the other hand, have fewer enemies and can live for more than 20 years.

The naked mole rat lives an even more protected lifestyle than do squirrels. The queens never come to the surface. Even the workers are exposed only when they need to shovel dirt to the earth’s surface.

A colony’s principal danger is other mole rats who may break into the tunnel system, testing the soldier caste’s defenses. Another risk to life is a kind of civil war that breaks out when a queen dies. Other females, intimidated into staying barren while the queen lived, regain their fertility and fight until one emerges victorious. But casualties are generally low, and presumably because of this relative safety, mole rats have evolved the ability to live more than 10 times longer than mice.

Mice are very prone to cancer; in some strains, 90 percent of them die of tumors. People have stronger defenses against cancer, as is necessary for a long-lived animal: the disease accounts for 23 percent of human mortality. But the mole rat has taken its anticancer defenses even further: it seems not to get the disease at all. “These animals have never been observed to develop any spontaneous neoplasms,” Vera Gorbunova and colleagues said in an article in the current Proceedings of the National Academy of Sciences.

Dr. Gorbunova, who works at the University of Rochester, has taken a first step toward understanding the genetic basis of the mole rat’s surprising immunity to cancer. She and her colleagues have found that the rats’ cells have a double system for inhibiting irregular proliferation, compared with the single system in human cells.

Normal human cells grown in a lab dish show behavior known as contact inhibition. Once the cells come in contact with one another, they form a single layer and stop dividing. Cancer cells, however, have thrown off that restraint and keep proliferating, forming one layer on top of another.

Dr. Gorbunova has found that both mole rat and human cells have the same system of contact inhibition, mediated in both species by a gene known as p27. But mole rats, in addition, have an early acting version of the same system and presumably use the p27 system just as a backup.

When mole rat cells in glassware make just a few contacts with one another, they stop growing and dividing. This early contact inhibition system is mediated by a gene called p16-ink4a. People also have the p16-ink4a gene, but it seems to play almost no role in contact inhibition of cells. The mole rat’s double system may be part of the reason for its remarkable immunity to cancer.

Another cell-level difference between the species is that mole rat cells maintain an active system for letting cells divide. Called telomerase, this system is switched off in mature human cells, presumably as a defense against cancer. Dr. Gorbunova believes the mole rat can afford to keep telomerase switched on, because its anticancer defenses are so good, and that the active telomerase may confer longer life on stem cells, which are responsible for repair and maintenance of the body’s tissues.

But Ronald da Pinho of Harvard Medical School, an expert on cancer and telomeres, disagreed, saying that inactive telomerase can be a cancer risk for human cells because it leads to genetic instability.

Increased life span in rodents is usually associated with caloric restriction, a diet with 30 percent fewer calories than usual. Laboratory mice and rats placed on such a diet at birth can live 40 percent longer than usual. Many other species have much the same reflex, and some biologists believe this is an ancient survival strategy, in which during times of famine the body’s reserves are switched to tissue maintenance, with the hope of riding out the bad times and breeding later.

Mole rats seem to lead something of a food-and-famine lifestyle. They live on tubers, the underground larders of nutrients laid down by plants in desert environments. One tuber can feed a colony of 100 mole rats for months. But even though they are careful to gnaw away at the tuber without killing the plant, the time comes when they must find another. Because the rats do not venture above ground, they must rely on the skill of their tunnel-digging work force to locate other tubers in the neighborhood.

The mole rats, presumably, get pretty hungry between tuber finds. Yet another of their quirks is that they have pushed the concept of recycling to extremes and will eat their own excrement. The continual alternation of food and famine might set off the same life-extending mechanisms in mole rats as does caloric restriction. But an expert on the genetics of caloric restriction, Leonard Guarente of the Massachusetts Institute of Technology noted that mole rats enjoyed long lives in captivity, where they were presumably well fed all the time.

Dr. Gorbunova plans to set up a colony of mole rats in her laboratory with plastic piping connecting a network of cages to serve as a tunnel system and carrots standing in for desert tubers. To understand human longevity and cancer, she said, “it’s important to study species other than mice.”

“I think,” she continued, “this is the beginning of a long journey.”

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